Diisocyanates have been estimated to cause occupational asthma (OA) in 5-15% of chronically exposed workers and deserve particular attention as they account for 26% of all OA cases. Because new cases are not entirely preventable, there is a need for screening methods for identifying workers at greatest risk to develop OA caused by these reactive chemicals. We have already identified a genotype and 3 genotype combinations of SNPs located on the IL-4Ra, IL-13 and CD-14 genes that are more frequent among French Canadian spray painters with proven OA caused by hexamethylene diisocyanate (HDI). We propose in specific Aim #1 to extend our Preliminary Studies by evaluating the aforementioned SNPs, HLA Class II alleles and polymorphisms associated with superoxide dismutase, glutathione-s-transferase, n-acetyl transferase enzymes to identify high-risk genotypes associated with the OA phenotype caused by diisocyanates and other reactive chemicals. Workers will be recruited from different background populations during evaluations for OA at five occupational inhalation challenge laboratories. In specific aim # 2, two subsets of 30 asymptomatic HDI paint workers identified with high risk genotypes and low risk genotypes will be assessed over 3 years for serial changes in methacholine responsiveness and markers of inflammation from induced sputum. Workers with confirmed HDI exposure will be assessed prior to and after 2 weeks of daily HDI exposure for changes in methacholine PC20, sputum cell counts, and sputum supernatants levels of IL-8, MMP-9, IL-5 and LTB4. Those workers showing increased expression in sputum parameters will be invited to return for controlled specific inhalation testing with HDI to confirm and validate methacholine and induced sputum results collected before and after workplace exposure. If high risk genotypes are validated as predictors of early inflammatory responses associated with diisocyanate exposure, this approach combining genetic screening and workplace monitoring can be further investigated as a prototypic model for early identification and prevention of OA due to reactive chemicals.